Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause that is characterized by a loss of immune tolerance against liver antigens, resulting in progressive destruction of the hepatic parenchyma and histologically by interface hepatitis, serologically by the presence of non-organ specific autoantibodies, biochemically by elevated aminotransferases and serum IgG, and clinically by the response to immunosuppressive treatment in the absence of other known causes of liver disease. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. Chronic hepatitis occurring predominantly in young women with arthralgias, myalgia, hepatosplenomegaly, amenorrhea, skin rashes, fluctuating course, and invariably fatal outcome Autoimmune hepatitis may present concurrently with other autoimmune diseases like Graves disease, rheumatoid arthritis, celiac disease, type I diabetes, ulcerative colitis, hemolytic anemia, and immune thrombocytopenia.
Synonyms of Autoimmune Hepatitis
- AIH
- autoimmune chronic active hepatitis
- lupoid hepatitis
Types of Autoimmune Hepatitis
There are two known types of autoimmune hepatitis.
- Type 1 – is distinguished by the presence of anti-smooth muscle antibodies (ASMA) with or without anti-nuclear antibodies (ANA).
- Type 2 – autoimmune hepatitis presents with positive anti-liver/anti-kidney microsome (anti-LMK) type 1 antibodies or anti-liver cytosol (anti-LC) type 1 antibodies.
Four subtypes of autoimmune hepatitis are recognized, but the clinical utility of distinguishing subtypes is limited.
- Type 1 AIH – Positive ANA and SMA,[rx] elevated immunoglobulin G (classic form, responds well to low dose steroids);
- Type 2 AIH – Positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3;
- Type 3 AIH – Positive antibodies against soluble liver antigen[14] (this group behaves like group 1)[15] (anti-SLA, anti-LP)
- AIH -with no autoantibodies detected – (~20%)(of debatable validity/importance)
Causes of Autoimmune Hepatitis
There is no specific evidence of the cause. Sixty percent of patients have chronic hepatitis but without serologic evidence of a viral infection. The disease is associated with anti-smooth muscle autoantibodies. [rx]
AIH occurs when your immune system mistakes your liver cells for foreign aggressors and creates antibodies to attack them. Doctors don’t know precisely why this occurs. However, certain risk factors have been identified, including:
- autoimmunity – the process of your immune system making autoantibodies, which ‘attack’ and damage your body’s own cells and organs
- environmental triggers – causes starting outside of the body; for example getting a virus, taking certain medications, or coming into contact with other toxins
- genetic predisposition – inheriting genes that may make it easier for a trigger to set off the disease.
- a family history of AIH
- history of bacterial or viral infections
- being female
- the use of certain medications, such as minocycline
Other autoimmune conditions can cause symptoms of liver disease and are also associated with the development of AIH. These diseases include:
- Grave’s disease
- thyroiditis
- ulcerative colitis
- type I diabetes
- rheumatoid arthritis
- scleroderma
- inflammatory bowel disease (IBD)
- systemic lupus erythematosus
- Sjögren’s syndrome
Symptoms of Autoimmune Hepatitis
Signs and symptoms in people with autoimmune hepatitis range from mild to severe depending on the amount of liver damage present. Symptoms are generally due to scarring of liver tissue (cirrhosis). Some people have no symptoms at first and are diagnosed after being evaluated for another health problem.[rx] Some of the most common signs and symptoms in people with autoimmune hepatitis may be nonspecific and include:[rx][rx][rx][rx]
- Most patients have nonspecific symptoms: fatigue, anorexia, nausea, weight loss, jaundice, pruritus, and amenorrhea
- Clinical manifestations of autoimmune hepatitis depend on how acute liver disease is at presentation, the stage of inflammation, or the complication of liver cirrhosis.
- The most common features of autoimmune hepatitis are fatigue, malaise, jaundice, abdominal pain, and sometimes, arthralgias.
- Fatigue (the most common symptom reported).
- Nausea.
- Loss of appetite.
- Diarrhea.
- Jaundice (yellowing of the skin and whites of the eyes).
- Loss of brain function (hepatic encephalopathy).
- Fluid in the abdomen (ascitesb).
- Swelling of the legs (edema).
- Easy bruising and bleeding.
- An enlarged spleen (splenomegaly).
- Gallstones.
- Itchy skin (pruritis) or skin rashes.
- Joint pain.
- Vomiting.
- Dark urine.
- Pale or gray-colored stools.
- Absence of menstrual periods in women (amenorrhea).
This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.
| Medical Terms | Other Names |
Learn More:
HPO ID
|
|---|---|---|
| 100% of people have these symptoms | ||
| Increased circulating IgG level | 0003237 | |
| 80%-99% of people have these symptoms | ||
| Anti-liver cytosolic antigen type 1 antibody positivity | 0030909 | |
| Antineutrophil antibody positivity | 0003453 | |
| Antinuclear antibody positivity | 0003493 | |
| Elevated hepatic transaminase |
High liver enzymes
|
0002910 |
| Liver kidney microsome type 1 antibody positivity | 0030908 | |
| Smooth muscle antibody positivity | 0003262 | |
| 30%-79% of people have these symptoms | ||
| Abdominal pain |
Pain in stomach
[ more ] |
0002027 |
| Arthralgia |
Joint pain
|
0002829 |
| Chronic fatigue |
Chronic extreme exhaustion
|
0012432 |
| Depressivity |
Depression
|
0000716 |
| Spider hemangioma | 0012522 | |
| 5%-29% of people have these symptoms | ||
| Acute hepatitis |
Acute liver inflammation
|
0200119 |
| Anxiety |
Excessive, persistent worry and fear
|
0000739 |
| Arthritis |
Joint inflammation
|
0001369 |
| Ascites |
Accumulation of fluid in the abdomen
|
0001541 |
| Cirrhosis |
Scar tissue replaces healthy tissue in the liver
|
0001394 |
| Diffuse hepatic steatosis | 0006555 | |
| Gastrointestinal hemorrhage |
Gastrointestinal bleeding
|
0002239 |
| Glomerulonephritis | 0000099 | |
| Increased total bilirubin |
High bili total
|
0003573 |
| Jaundice |
Yellow skin
[ more ] |
0000952 |
| Sclerosing cholangitis | 0030991 | |
| Splenomegaly |
Increased spleen size
|
0001744 |
| Thyroiditis |
Thyroid gland inflammation
|
0100646 |
| Ulcerative colitis | 0100279 | |
| Vitiligo |
Blotchy loss of skin color
|
0001045 |
| 1%-4% of people have these symptoms | ||
| Fulminant hepatitis | 0004787 | |
| Hepatocellular carcinoma | 0001402 | |
| Viral hepatitis | 0006562 | |
Diagnosis of Autoimmune Hepatitis
A multi-pronged approach is used to make a diagnosis. This approach includes determining symptoms, laboratory tests, and biopsies, as no single diagnostic test is pathognomonic for autoimmune hepatitis. Marked elevation of serum transaminases (AST, ALT) and gamma-globulin is common; elevation in alkaline phosphatase is less common. The serum levels of AST, ALT, and gamma globulin reflect disease severity and immediate prognosis at presentation.
- Diagnosis is based on combinations of clinical, laboratory, and histological features
- Revised diagnostic International Autoimmune Hepatitis Group (IAHG) scoring system (rx):
- Complex system evaluating 11 clinical, laboratory, and histological factors
- For research purposes – not designed for clinical practice
- Simplified diagnostic IAHG scoring system (rx):
- Simple system evaluating 4 laboratory and histological factors: serum autoantibodies, IgG, liver histology and viral hepatitis serology
- Cutoff values for probable and definite AIH are 6 points (88% sensitivity and 97% specificity) and 7 points (81% sensitivity and 99% specificity), respectively
- AIH subtypes depend on autoantibody serology:
- Type 1: positive for antinuclear antibody (ANA) or anti-smooth muscle antibody (SMA); 10% have other autoimmune disorders
- Type 2: positive for anti-liver-kidney microsomal (LKM) antibody or anti liver cytosol type 1 (LC1) antibody-positive; often presents with acute or fulminant hepatitis; 17% have other autoimmune disorders
- About 10% of AIH shows coexisting features of the immune-mediated biliary disease (overlap syndrome) or are associated with atypical features (variant syndrome)
- Overlap syndrome: AIH primary biliary cirrhosis and AIH primary sclerosing cholangitis
- Variant syndromes: seronegative AIH and antimitochondrial antibody (AMA) positive AIH
Laboratory
- Serum autoantibodies(rx):
- ANA – positive in 75% of type 1 AIH; not associated with disease course or outcome
- Anti-SMA – positive in 95% of type 1 AIH; not associated with disease course or outcome
- Anti-LKM – diagnostic for type 2 AIH; associated with younger age at presentation, fulminant hepatic failure, and partial IgA deficiency
- Anti-LC1 – diagnostic for type 2 AIH; associated with more severe inflammation and rapid progression to cirrhosis
- Anti soluble liver antigen (SLA) / live pancreas (LP) – positive in 20 – 50% of AIH; associated with more severe disease, treatment dependence, relapse after drug withdrawal, and need for transplantation
- Serum immunoglobulin G (IgG) – not only a diagnostic marker but also a marker for monitoring treatment response (rx)
- Autoantibodies – A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased immunoglobulin G level. The presence of anti-mitochondrial antibody is more suggestive of primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value.[rx]
- Blood tests – Testing a sample of your blood for antibodies can distinguish autoimmune hepatitis from viral hepatitis and other conditions with similar symptoms. Antibody tests also help pinpoint the type of autoimmune hepatitis you have.
- Liver function tests – These check for inflammation or damage to your liver.
- Coagulation panel – This test looks at how well the clotting proteins are working.
- Electrolyte panel – Checks to see if you have an electrolyte imbalance.
- Other liver tests – These are done to check for other possible types of liver disease.
- CT scan – This is more detailed than a standard X-ray. It can show detailed images of any part of the body, including the bones, muscles, fat, and organs. It uses both X-rays and computer technology to make horizontal images (often called slices) of the body.
- MRI – This test makes detailed pictures of organs and structures inside your body. It uses a magnetic field and pulses of radio wave energy. A dye may be shot or injected into your vein. The dye helps the liver and other organs in the belly to be seen more clearly on the scan.
- Ultrasound – This uses high-frequency sound waves to create a picture of the organs. It can also check blood flow in blood vessels.
- Liver biopsy – Doctors perform a liver biopsy to confirm the diagnosis and to determine the degree and type of liver damage. During the procedure, a small amount of liver tissue is removed, using a thin needle that’s passed into your liver through a small incision in your skin. The sample is then sent to a laboratory for analysis.
- Anti-liver cytosol type I, anti-soluble liver antigen (SLA) antibodies, and perinuclear antineutrophil cytoplasmic antibodies (pANCA) can also be associated with autoimmune hepatitis. [rx]Conversely, anti-mitochondrial antibodies are more commonly seen with primary biliary cirrhosis and are usually absent in autoimmune hepatitis; however, they can be present in those with overlapping syndromes. Atypical perinuclear antineutrophil cytoplasmic antibodies are commonly associated with type-1 autoimmune hepatitis and primary sclerosing cholangitis. Anti-LKM1 is common in type-1 autoimmune hepatitis and mainly observed in children.
- Anti-SLA antibodies – are more useful from a prognostic standpoint as these are associated with more severe disease, treatment failure, and higher relapse rates. A liver biopsy is required for both diagnosis and staging of autoimmune hepatitis.
Treatment Of Autoimmune Hepatitis
Treatment (which is based on supportive care) is as follows
- Antiviral medications (if virus causes)
- Antibiotics, (if bacteria cause)
- Steroids are used to reduce brain swelling
- Sedatives for restlessness
- Acetaminophen for fever
- Occupational and physical therapy (if the brain is affected post-infection)
Medications
autoimmune hepatitis is a rare condition with no randomized controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide, and rituximab.[rx]
- Corticosteroids – are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like autoimmune hepatitis. Because most patients respond to corticosteroids or glucocorticoid immunosuppressant treatment, this condition is now also referred to as steroid-responsive autoimmune hepatitis. Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days or prednisone is usually administered orally at 2 mg/kg/day (up to a maximum of 60 mg/day), azathioprine is administered at the initial dose of 1 mg/kg/day, which can be further increased up to 2.5 mg/kg/day until sustained biochemical remission is achieved.[rx]
- Budesonide – has been shown to be more effective in inducing remission than prednisone, and result in fewer adverse effects.[17]
- Immunoglobulin infusion(IVIG) – Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune hepatitis[rx] [rx] Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.[rx][rx]
- Plasmapheresis – can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual. [rx]
- Biological Drugs – Rituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.[rx]
- Anti Seizure Drugs – management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of autoimmune hepatitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects.[rx] Gradual reduction of autoimmune hepatitis is possible during follow-up and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx][rx]
- Benzodiazepines and electroconvulsive therapy – have been utilized to treat catatonia. Abnormal movements associated with this autoimmune hepatitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine. ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx][rx]
- Antiviral Medication – Herpes simplex encephalitis is the commonest autoimmune hepatitis. Any patient who presented with clinical features of autoimmune hepatitis should be treated empirically with IV acyclovir, pending the result of autoimmune hepatitis results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of autoimmune hepatitis is often due to autoimmune hepatitis triggered by autoimmune hepatitis. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary autoimmune hepatitis.[rx]
- Liver transplant – When medications don’t halt the progress of the disease or you develop irreversible scarring (cirrhosis) or liver failure, the remaining option is a liver transplant. During a liver transplant, your diseased liver is removed and replaced with a healthy liver from a donor. Liver transplants most often use livers from deceased organ donors. In some cases, a living donor liver transplant can be used. During a living donor liver transplant, you receive only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.
Current Alternative Treatments
Although conventional treatment with steroids ± azathioprine allows achieving remission in most patients, in cases of initial treatment failure or multiple relapses during tapering or discontinuation attempts, alternative therapies are often proposed.
Cyclosporine (CSA) is a powerful immunosuppressant that has been successfully used in patients with JAIH as a short-term initial treatment alternative to steroid-azathioprine or as a salvage treatment (rx, rx). The main side effects of CSA include nephrotoxicity, arterial hypertension, and gastrointestinal and neurological toxicity. Minor but frequent side effects are Hypertrichosis and gum hypertrophy; although transient they occasionally can influence adherence to treatment. Since 1985, the use of CSA has been documented in 133 adults with autoimmune hepatitis. CSA was used as salvage therapy and showed an overall positive response of any degree in about 93% of patients and a negative response, defined as no response, non-compliance, or drug intolerance in 7% (rx, rx).
Regarding pediatric patients, there are only five major publications in which CSA is mostly administered for short periods, mainly to induce remission, as a bridge to conventional treatment (rx, rx).
Furthermore, the effectiveness of CSA was similar to steroids as salvage therapy in children with JAIH and liver failure (rx). Prolonged CSA treatment for autoimmune pediatric liver disorders was first reported in 2004 with an excellent safety profile (rx), confirmed also in a recent follow-up study (rx).
A recent meta-analysis by Zizzo et al. confirmed that CSA has the highest short-term response rate (86%) in conventional treatment-refractory children with autoimmune hepatitis (rx).
Besides CSA, a wide range of immunosuppressive drugs has been used in small series of children (rx).
Mycophenolate Mofetil (MFM) is the second most effective drug for conventional treatment-refractory children with JAIH after cyclosporine (36% remission rate at 6 months) (rx). The main concern is the use of MMF is the lack of knowledge regarding its therapeutic range and toxic threshold; moreover, MFM is more expensive than azathioprine and is absolutely contraindicated during pregnancy.
Recently, Budesonide, a corticosteroid with potentially fewer side effects than other glucocorticoids, emerged as an alternative first-line treatment in association with azathioprine. When comparing the effects of budesonide vs. prednisone, both in combination with azathioprine, budesonide did cause fewer side effects than prednisone; however, after 12 months, only 46% of the patients treated with budesonide achieved complete remission (rx). The low proportion of remission observed in this study does not support its use as a first-line treatment of AIH (rx, rx).
mTOR inhibitors as sirolimus or everolimus have been used as salvage therapy with good results in few published adult patients (rx, rx).
Liver transplantation represents a therapeutic option for a small proportion of patients under two main circumstances: patients presenting with acute liver failure that does not respond to salvage therapy with rescue immunosuppression, and patients with cirrhosis with end-stage liver disease.
Next steps
Tips to help you get the most from a visit to your healthcare provider:
- Know the reason for your visit and what you want to happen.
- Before your visit, write down questions you want answered.
- Bring someone with you to help you ask questions and remember what your provider tells you.
- At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
- Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
- Ask if your condition can be treated in other ways.
- Know why a test or procedure is recommended and what the results could mean.
- Know what to expect if you do not take the medicine or have the test or procedure.
- If you have a follow-up appointment, write down the date, time, and purpose for that visit.
- Know how you can contact your provider if you have questions.
References